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In this work we study the properties of segregation processes modeled by a family of equations L(ui)(x) = ui(x)Fi(u1, ..., uK)(x), i = 1, ..., K, where Fi(u1,...,uK)(x) is a non-local factor that takes into consideration the values of the functions uj in a full neighborhood of x. We consider as a model problem ... where ε is a small parameter and H(ujε) (x) is for instance .... Here B1 (x) is the unit ball centered at x with respect to a smooth, uniformly convex norm ρ in ℝn. Heuristically, this will force the populations to stay at ρ-distance 1 from each other as ε → 0. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is a significant health concern characterized by reduced blood flow to the heart muscle, primarily due to the buildup of atherosclerotic plaques in the coronary arteries. This process begins with endothelial injury, leading to a cascade of biological responses contributing to plaque formation. Endothelial injury attracts the migration of monocytes which differentiate into macrophages upon uptake of oxidized low-density lipoproteins, changing into lipid-laden macrophage or "foam cells." The process of plaque formation is influenced by many factors which have been studied extensively in literature such as smoking, hypertension, and diabetes mellitus. Chronic inflammatory illnesses are often associated with a high prevalence of coronary artery syndromes, prompting the evaluation of markers of inflammation such as white blood cell count and inflammatory markers as independent risk factors for CAD. White blood cells play a remarkable role in the pathophysiology of disease formation and progression. The article below aims to discuss the pathophysiology and epidemiology of leukocytosis as a risk factor for CAD., Competing Interests: Correspondence: Wilbert S. Aronow, MD, FACC, FAHA, Departments of Disclosures: The authors have no conflicts of interest to report, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: High-risk neonates continuing to need enteral nutrition, but otherwise medically ready for discharge home from the NICU, are often offered ongoing hospitalization for nasogastric tube (NGT) feeding, versus discharge after placement of gastrostomy tube. Our group developed an interdisciplinary algorithm to support a third option-discharge home with enteral nutrition via NGT. Our objective was to develop a cross-institutional and interdisciplinary pathway to optimize outcomes for neonates discharged with NGTs., Methods: A program to support home NGT feeding use was created, "Passport Home Program," based upon feedback from parents, nurses, speech-language pathologists, otolaryngologists, and neonatal intensivists, amongst others, spanning four hospitals across our health system., Results: Standardized educational materials for caregivers of neonates requiring ongoing NGT feeding on discharge were created and consist of an in-hospital curriculum with specific competency thresholds, including demonstrating NGT replacement and confirmation with pH test strips. A discharge kit, including a QR code for a video reviewing safe techniques for home NGT placement, is distributed, along with support staff contact information. Members of an emergency department were trained in neonatal NGT replacement in case of issues after business hours. Each patient is followed in a dedicated outpatient multi-disciplinary clinic., Discussion: This is an interdisciplinary and multi-institutional effort to standardize a pathway for neonates discharged home from the NICU with NGTs. This has the potential to lead to earlier discharge, better outcomes for patients and families, as well as lower costs. This best practice algorithm serves as an example pathway applicable across fields of medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A double-hit lymphoma is a high-grade B-cell lymphoma (HGBCL) with MYC and BCL2/BCL6 rearrangements. It is characterized by a rapidly progressive advanced disease, high rates of central nervous involvement (CNS), refractoriness to conventional chemotherapy, and poorer clinical outcomes. Carcinomatous meningitis is a condition in which cancer cells metastasize to the meninges without involving the brain parenchyma; this phenomenon has also been reported in the literature by other terms like "leptomeningeal meningitis," "leptomeningeal carcinomatosis," "leptomeningeal metastasis," or "neoplastic meningitis." This form of CNS involvement has been described as an infrequent complication with the trajectory of this aggressive lymphoma. We report an illuminating case of a 63-year-old male diagnosed with double-hit lymphoma, which was complicated by fatal carcinomatous meningitis., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Swaminathan et al.)

Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse reaction (SCAR) characterized by an extensive skin rash associated with visceral organ involvement, fever, eosinophilia, atypical lymphocytosis, and lymphadenopathy. Toxic epidermal necrolysis (TEN) is a more severe, distinct adverse cutaneous reaction that causes extensive necrosis and detachment of the epidermis, involving over 30% of the body surface area (BSA). Hemophagocytic lymphohistiocytosis (HLH), a form of excessive immune activation, is known to be associated with SCARs such as DRESS. We present a peculiar case of overlap between different SCARs to reiterate their gravity, a severe form of DRESS triggered by the use of allopurinol overlapping with the aggressive TEN possibly from interaction with vancomycin administered for severe sepsis, which was complicated by a fatal case of HLH., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Swaminathan et al.)

Purpose: To study the biological relationship between congenital lung malformations (CLMs) and malignancy., Methods: Biopsies of 12 CPAMs, 6 intralobar sequestrations and 2 extralobar sequestrations were analyzed through whole-genome sequencing. Blood samples from 10 patients were used to confirm or exclude somatic mosaicism. Putative somatic Single Nucleotide Variants (SNVs) were called for each malformed sample with a Panel of Normals built with control DNA samples extracted from blood. The variants were subsequently confirmed by Sanger sequencing and searched, whenever possible, in the blood samples of patients., Results: All CLMs but one presented a signature of genomic instability by means of multiple clusters of cells with gene mutations. Seven tumor transformation-related SNVs were detected in 6/20 congenital lung malformations. Four very rare in the general population SNVs were found in a region previously linked to lung cancer in 5p15.33, upstream of TERT oncogene. Furthermore, we identified missense genetic variants, whose tumorigenic role is well known, in the RET, FANCA and MET genes., Conclusions: Genomic instability in 95% of CLMs and genetic variants linked to tumor development in 30% of them, regardless of histopathology, are predisposing factors to malignancy, that combined with exposure to carcinogens, might trigger the development of malignancy and explain the association between CLMs and lung cancer., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

EGFR aberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (EGFR-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma, and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with the histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry. Lesions were from 10 males and 4 females with a mean age of 3 years (range, 0.3-14) and occurred subcutaneously in the upper limbs (n = 5), lower limbs (n = 3), back/thorax (n = 5), and the nasal cavity (n = 1). Eleven were cured by surgery, including 1 relapsed case. Two patients were lost to follow-up. One case was very recent, and the patient was biopsied. Histologically, the lesions showed a wide spectrum varying from classic FHI (n = 9) to IFS (n = 1) or lipofibromatosis-like tumors (LFT-like) (n = 2) or dermatofibrosarcoma protuberans-like (DFSP-like) (n = 1) to a predominantly myxoid spindle cell lesion (n = 1). Immunohistochemically, all neoplasms stained with CD34, whereas S100 was positive in 2/14. EGFR expression was observed in 9/10 cases. Molecularly, the IFS and 1 LFT-like harbored EGFR-KDD, whereas an exon 20 mutation was identified in all FHI, 1 LFT-like, the DFSP-like, and in predominant myxoid spindle cell lesion. By DNAmp, all but 2 cases formed a well-defined cluster, demonstrating that these lesions are also epigenetically related. In conclusion, EGFR kinase domain aberrations found in FHI, IFS, LFT-like, DFSP-like, and a spindle cell lesion with a predominant myxoid stroma of children and adolescents showed that these neoplasms with a broad morphologic spectrum belong to the group of protein kinase-related lesions with a distinct epigenetic signature. Molecular analyses, including DNAmp, help to identify and characterize this emerging category and become mandatory when targeted treatment is considered., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

A patient's demographics often guide healthcare providers toward clues to a diagnosis. A recent travel history becomes an essential piece of the puzzle when there is a high suspicion of an infectious cause. When a patient walks into the hospital after having traveled to or from a resource-poor country with systemic afflictions, a physician's mind quickly jumps to infectious causes, and in most circumstances, it proves to be correct. We report an interesting case of a 28-year-old male from Guatemala who experienced acute gastrointestinal (GI) symptoms. Previous research in this field has shown that patients with inflammatory bowel disease (IBD) are prone to a slew of GI infections. Interestingly, our patient's presenting symptoms were initially attributed to "infections," but a thorough investigation revealed an unexpected twist of events. Our patient presented with multiple GI infections after the usual triggers, which masqueraded the coexistence of underlying primary sclerosing cholangitis and ulcerative colitis for a short course but were diagnosed promptly after a thorough workup., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Swaminathan et al.)

Acinar dysplasia (AcDys) of the lung is a rare lethal developmental disorder in neonates characterized by severe respiratory failure and pulmonary arterial hypertension refractory to treatment. Recently, abnormalities of TBX4-FGF10-FGFR2-TMEM100 signaling regulating lung development have been reported in patients with AcDys due to heterozygous single-nucleotide variants or copy-number variant deletions involving TBX4 , FGF10 , or FGFR2 . Here, we describe a female neonate who died at 4 hours of life due to severe respiratory distress related to AcDys diagnosed by postmortem histopathologic evaluation. Genomic analyses revealed a novel deleterious heterozygous missense variant c.728A>C (p.Asn243Thr) in TBX4 that arose de novo on paternal chromosome 17. We also identified 6 candidate hypomorphic rare variants in the TBX4 enhancer in trans to TBX4 coding variant. Gene expression analyses of proband's lung tissue showed a significant reduction of TMEM100 expression with near absence of TMEM100 within the endothelium of arteries and capillaries by immunohistochemistry. These results support the pathogenicity of the detected TBX4 variant and provide further evidence that disrupted signaling between TBX4 and TMEM100 may contribute to severe lung phenotypes in humans, including AcDys., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Five-year glioblastoma (GBM) survivors (LTS) are the minority of the isocitrate dehydrogenase (IDH)-wild-type GBM patients, and their molecular fingerprint is still largely unexplored. This multicenter retrospective study analyzed a large LTS-GBM cohort from nine Italian institutions and molecularly characterized a subgroup of patients by mutation, DNA methylation (DNAm) and copy number variation (CNV) profiling, comparing it to standard survival GBM. Mutation scan allowed the identification of pathogenic variants in most cases, showing a similar mutational spectrum in both groups, and highlighted TP53 as the most commonly mutated gene in the LTS group. We confirmed DNAm as a valuable tool for GBM classification with a diagnostic refinement by using brain tumor classifier v12.5. LTS were more heterogeneous with more cases classified as diffuse pediatric high-grade glioma subtypes and having peculiar CNVs. We observed a global higher methylation in CpG islands and in gene promoters of LTS with methylation levels of distinct gene promoters correlating with prognosis., Competing Interests: Declaration of competing interest The authors declared that have no competing interest., (Copyright © 2024. Published by Elsevier B.V.)

In vitro models of pediatric brain tumors (pBT) are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor. We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples, including 155 tumors and 86 pBT-derived cell cultures, considering serum vs serum-free conditions, late vs early passages, and dimensionality (2D vs 3D cultures). We performed a t-SNE classification and identified differentially methylated regions in tumors compared to cell models. Early cell cultures recapitulate the original tumor, but serum media and 2D culturing were demonstrated to significantly contribute to the divergence of DNAm profiles from the parental ones. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration. In conclusion, DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors., (© 2024. The Author(s).)

PATZ1-rearranged sarcomas are well-recognized tumors as part of the family of round cell sarcoma with EWSR1-non-ETS fusions. Whether PATZ1-rearranged central nervous system (CNS) tumors are a distinct tumor type is debatable. We thoroughly characterized a pediatric series of PATZ1-rearranged CNS tumors by chromosome microarray analysis (CMA), DNA methylation analysis, gene expression profiling and, when frozen tissue is available, optical genome mapping (OGM). The series consisted of 7 cases (M:F=1.3:1, 1-17 years, median 12). On MRI, the tumors were supratentorial in close relation to the lateral ventricles (intraventricular or iuxtaventricular), preferentially located in the occipital lobe. Two major histologic groups were identified: one (4 cases) with an overall glial appearance, indicated as "neuroepithelial" (NET) by analogy with the corresponding methylation class (MC); the other (3 cases) with a predominant spindle cell sarcoma morphology, indicated as "sarcomatous" (SM). A single distinct methylation cluster encompassing both groups was identified by multidimensional scaling analysis. Despite the epigenetic homogeneity, unsupervised clustering analysis of gene expression profiles revealed 2 distinct transcriptional subgroups correlating with the histologic phenotypes. Interestingly, genes implicated in epithelial-mesenchymal transition and extracellular matrix composition were enriched in the subgroup associated to the SM phenotype. The combined use of CMA and OGM enabled the identification of chromosome 22 chromothripsis in all cases suitable for the analyses, explaining the physical association of PATZ1 to EWSR1 or MN1. Six patients are currently disease-free (median follow-up 30 months, range 12-92). One patient of the SM group developed spinal metastases at 26 months from diagnosis and is currently receiving multimodal therapy (42 months). Our data suggest that PATZ1-CNS tumors are defined by chromosome 22 chromothripsis as causative of PATZ1 fusion, show peculiar MRI features (eg, relation to lateral ventricles, supratentorial frequently posterior site), and, although epigenetically homogenous, encompass 2 distinct histologic and transcriptional subgroups., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Malignant peripheral nerve sheath tumors (MPNSTs) account for 3-10% of pediatric sarcomas, 50% of which occur in neurofibromatosis type 1 (NF1). Sporadic MPNSTs diagnosis may be challenging due to the absence of specific markers, apart from immunohistochemical H3K27me3 loss. DNA methylation (DNAm) profiling is a useful tool for brain and mesenchymal neoplasms categorization, and MPNSTs exhibit a specific DNAm signature. An MPNST-like group has recently been recognized, including pediatric tumors with retained H3K27me3 mark and clinical/histological features not yet well explored. This study aims to characterize the DNAm profile of pediatric/juvenile MPNSTs/MPNST-like entities and its diagnostic/prognostic relevance., Results: We studied 42 tumors from two groups. Group 1 included 32 tumors histologically diagnosed as atypical neurofibroma (ANF) (N = 5) or MPNST (N = 27); group 2 comprised 10 tumors classified as MPNST-like according to Heidelberg sarcoma classifier. We performed further immunohistochemical and molecular tests to reach an integrated diagnosis. In group 1, DNAm profiling was inconclusive for ANF; while, it confirmed the original diagnosis in 12/27 MPNSTs, all occurring in NF1 patients. Five/27 MPNSTs were classified as MPNST-like: Integrated diagnosis confirmed MPNST identity for 3 cases; while, the immunophenotype supported the change to high-grade undifferentiated spindle cell sarcoma in 2 samples. The remaining 10/27 MPNSTs variably classified as schwannoma, osteosarcoma, BCOR-altered sarcoma, rhabdomyosarcoma (RMS)-MYOD1 mutant, RMS-like, and embryonal RMS or did not match with any defined entity. Molecular analysis and histologic review confirmed the diagnoses of BCOR, RMS-MYOD1 mutant, DICER1-syndrome and ERMS. Group 2 samples included 5 high-grade undifferentiated sarcomas/MPNSTs and 5 low-grade mesenchymal neoplasms. Two high-grade and 4 low-grade lesions harbored tyrosine kinase (TRK) gene fusions. By HDBSCAN clustering analysis of the whole cohort we identified two clusters mainly distinguished by H3K27me3 epigenetic signature. Exploring the copy number variation, high-grade tumors showed frequent chromosomal aberrations and CDKN2A/B loss significantly impacted on survival in the MPNSTs cohort., Conclusion: DNAm profiling is a useful tool in diagnostic work-up of MPNSTs. Its application in a retrospective series collected during pre-molecular era contributed to classify morphologic mimics. The methylation group MPNST-like is a 'hybrid' category in pediatrics including high-grade and low-grade tumors mainly characterized by TRK alterations., (© 2024. The Author(s).)

Background: Neonatal encephalopathy (NE) continues to be a significant risk for death and disability. To address this risk, regional guidelines were developed with the support of a malpractice insurance patient safety organization. A NE registry was also established to include 14 centers representing around 50% of deliveries in the state of Massachusetts. The aim of this study was to identify areas of variation in practice that could benefit from quality improvement projects., Methods: This manuscript reports on the establishment of the registry and the primary findings to date., Results: From 2018 to 2020, 502 newborns with NE were evaluated for Therapeutic Hypothermia (TH), of which 246 (49%) received TH, representing a mean of 2.91 per 1000 live births. The study reports on prenatal characteristics, delivery room resuscitation, TH eligibility screening, and post-natal management of newborns with NE who did and did not receive TH., Conclusions: The registry has allowed for the identification of areas of variation in clinical practices, which have guided ongoing quality improvement projects. The authors advocate for the establishment of local and regional registries to standardize and improve NE patient care. They have made the registry data collection tools freely available for other centers to replicate this work., Impact: Malpractice insurance companies can take an active role in supporting clinicians in establishing clinical practice guidelines and regional registries. Establishing a collaborative regional neonatal encephalopathy (NE) registry is feasible. Data Collection tools for a NE registry have been made publicly available to be adopted and replicated by other groups. Establishing a regional NE registry allowed for the identification of gaps in knowledge, variations in practice, and the opportunity to advance care through quality improvement projects., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Early in the COVID-19 pandemic, many birth hospitals separated SARS-CoV-2-positive mothers from their newborn infants and advised against breastfeeding to decrease postnatal SARS-CoV-2 transmission. Information on how these practices impacted breastfeeding postdischarge is limited. Objectives: In a statewide sample of SARS-CoV-2-positive mothers, we aimed to determine the extent to which (1) mother-infant separation and (2) a lack of breastfeeding initiation in-hospital were associated with breast milk feeding postdischarge. Design/Methods: From 11 birthing hospitals in Massachusetts, we identified 187 women who tested positive for SARS-CoV-2 from 14 days before to 72 hours after delivery (March 1-July 31, 2020) and their newborn infants. We abstracted chart data from the delivery hospitalization on main exposure variables (mother-infant separation, in-hospital breast milk feeding [expressed milk feeding and/or direct breastfeeding]) and from outpatient visits until 30 days postdischarge. We evaluated associations of in-hospital practices with outcomes up to 30 days postdischarge, adjusting for confounders using multivariable logistic and linear regression. Results: Mother-infant separation in-hospital was associated with a shorter duration of any breast milk feeding (regression coefficient estimate - 5.29 days, 95% confidence intervals [CI] [-8.89 to -1.69]). Direct breastfeeding in-hospital was associated with higher odds of any breast milk feeding (adjusted odds ratios [AOR] 5.68, 95% CI [1.65-23.63]) and direct breastfeeding (AOR 8.19, 95% CI [2.99-24.91]) postdischarge; results were similar for any breast milk feeding in-hospital. Conclusions: Perinatal hospital care practices implemented early in the COVID-19 pandemic, specifically mother-infant separation and prevention of breast milk feeding initiation, were associated with adverse effects on breast milk feeding outcomes assessed up to 1 month postdischarge.

Objective: We leveraged the Massachusetts perinatal quality collaborative (PQC) to address the COVID-19 pandemic. Our goals were to: (1) implement perinatal practices thought to reduce mother-to-infant SARS-CoV-2 transmission while limiting disruption of health-promoting practices and (2) do so without inequities attributable to race/ethnicity, language status, and social vulnerability., Methods: Main outcomes were cesarean and preterm delivery, rooming-in, and breastfeeding. We examined changes over time overall and according to race/ethnicity, language status, and social vulnerability from 03/20-07/20 at 11 hospitals., Results: Of 255 mothers with SARS-CoV-2, 67% were black or Hispanic and 47% were non-English speaking. Cesarean decreased (49% to 35%), while rooming-in (55% to 86%) and breastfeeding (53% to 72%) increased. These changes did not differ by race/ethnicity, language, or social vulnerability., Conclusions: Leveraging the Massachusetts PQC led to rapid changes in perinatal care during the COVID-19 crisis in a short time, representing a novel use of statewide PQC structures., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background and Objectives: The treatment of asymptomatic patients with congenital pulmonary malformations (CPMs) remains controversial, partially because the relationship between congenital lung malformations and malignancy is still undefined. Change in methylation pattern is a crucial event in human cancer, including lung cancer. We therefore studied all differentially methylated regions (DMRs) in a series of CPMs in an attempt to find methylation anomalies in genes already described in association with malignancy., Methods: The DNA extracted from resected congenital lung malformations and control lung tissue was screened using Illumina MethylationEPIC arrays. Comparisons between the group of malformed samples or the malformed samples of same histology or each malformed sample and the controls and between a pleuropulmonary blastoma (PPB) and controls were performed. Moreover, each malformed sample was pairwise compared with its respective control. All differentially methylated regions (DMRs) with an adjusted p-value <0,05 were studied., Results: Every comparison highlighted a number of DMRs closed to genes involved either in cell proliferation or in embryonic development or included in the Cancer Gene Census. Their abnormal methylation had been already described in lung tumors., Conclusions: Methylation anomalies already described in lung tumors and also shared by the PPB were found in congenital lung malformations, regardless the histology. The presence of methylation abnormalities is suggestive of a correlation between congenital lung malformations and some step of malignant transformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Patrizi, Pederiva and d’Adamo.)

Importance: The incidence of mother-to-newborn SARS-CoV-2 transmission appears low and may be associated with biological and social factors. However, data are limited on the factors associated with neonatal clinical or viral testing outcomes., Objective: To ascertain the percentage of neonates who were born to mothers with positive SARS-CoV-2 test results during the birth hospitalization, the clinical and sociodemographic factors associated with neonatal test result positivity, and the clinical and virological outcomes for newborns during hospitalization and 30 days after discharge., Design, Setting, and Participants: This multicenter cohort study included 11 academic or community hospitals in Massachusetts and mother-neonate dyads whose delivery and discharge occurred between March 1, 2020, and July 31, 2020. Eligible dyads were identified at each participating hospital through local COVID-19 surveillance and infection control systems. Neonates were born to mothers with positive SARS-CoV-2 test results within 14 days before to 72 hours after delivery, and neonates were followed up for 30 days after birth hospital discharge., Exposures: Hypothesized maternal risk factors in neonatal test result positivity included maternal COVID-19 symptoms, vaginal delivery, rooming-in practice, Black race or Hispanic ethnicity, and zip code-derived social vulnerability index. Delivery indicated by worsening maternal COVID-19 symptoms was hypothesized to increase the risk of adverse neonatal health outcomes., Main Outcomes and Measures: Primary outcomes for neonates were (1) positive SARS-CoV-2 test results, (2) indicators of adverse health, and (3) clinical signs and viral testing. Test result positivity was defined as at least 1 positive result on a specimen obtained by nasopharyngeal swab using a polymerase chain reaction-based method. Clinical and testing data were obtained from electronic medical records of nonroutine health care visits within 30 days after hospital discharge., Results: The cohort included 255 neonates (mean [SD] gestational age at birth, 37.9 [2.6] weeks; 62 [24.3%] with low birth weight or preterm delivery) with 250 mothers (mean [SD] age, 30.4 [6.3] years; 121 [48.4%] were of Hispanic ethnicity). Of the 255 neonates who were born to mothers with SARS-CoV-2 infection, 225 (88.2%) were tested for SARS-CoV-2 and 5 (2.2%) had positive results during the birth hospitalization. High maternal social vulnerability was associated with higher likelihood of neonatal test result positivity (adjusted odds ratio, 4.95; 95% CI, 1.53-16.01; P = .008), adjusted for maternal COVID-19 symptoms, delivery mode, and rooming-in practice. Adverse outcomes during hospitalization were associated with preterm delivery indicated by worsening maternal COVID-19 symptoms. Of the 151 newborns with follow-up data, 28 had nonroutine clinical visits, 7 underwent SARS-CoV-2 testing, and 1 had a positive result., Conclusions and Relevance: The findings emphasize the importance of both biological and social factors in perinatal SARS-CoV-2 infection outcomes. Newborns exposed to SARS-CoV-2 were at risk for both direct and indirect adverse health outcomes, supporting efforts of ongoing surveillance of the virus and long-term follow-up.

Variants in tank-binding kinase 1 (TBK1) are responsible for a significant proportion of amyotrophic lateral sclerosis (ALS) cases. In the present study, we analyzed variants in TBK1 extracted by targeted sequencing of 32 genes in a group of 406 Italian patients with ALS. We identified 7 different TBK1 variants in 7 sporadic cases, resulting in a frequency of 1.7%. Three patients had missense variants (p.R357Q, p.R358H, and p.R724C), one patient had a small deletion (p.E618del), and 3 had truncating variants (p.Y482*, p.R229*, and p.N681*). Notably, we found that 4 patients had an additional variant in ALS-related genes: 2 in OPTN and 2 in the 3'UTR region of FUS. By studying an independent group of 7 TBK1-mutated patients previously reported, we found another variant in the 3'UTR region of FUS in one patient. The presence of a second variant in TBK1 variant carriers is an interesting finding that needs to be investigated in larger cohorts of patients. These findings suggest that TBK1 belongs to the category of genes conferring a significantly increased risk but not sufficient to cause disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

KAT6B sequence variants have been identified in both patients with the Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and in the genitopatellar syndrome (GPS). In SBBYSS, they were reported to affect mostly exons 16-18 of KAT6B, and the predicted mechanism of pathogenesis was haploinsufficiency or a partial loss of protein function. Truncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant-negative effect of the mutated protein, most likely. Although SBBYSS and GPS have been initially considered allelic disorders with distinctive genetic and clinical features, there is evidence that they represent two ends of a spectrum of conditions referable as KAT6B-related disorders. We detected a de novo truncating variant within exon 7 of KAT6B in a 8-year-old female who presented with mild intellectual disability, facial dysmorphisms highly consistent with SBBYSS, and skeletal anomalies including exostosis, that are usually considered component manifestations of GPS. Following the clinical diagnosis driven by the striking facial phenotype, we analyzed the KAT6B gene by NGS techniques. The present report highlights the pivotal role of clinical genetics in avoiding clear-cut genotype-phenotype categories in syndromic forms of intellectual disability. In addition, it further supports the evidence that a continuum exists within the clinical spectrum of KAT6B-associated disorders., (© 2017 Wiley Periodicals, Inc.)

The neonatal EEG remains one of oldest, yet most valuable, diagnostic and prognostic tests in neonates. The goals of this study were to determine the relationships between the morphology, frequency, and distribution of ictal discharges in the neonatal EEG with age, EEG background activity, and etiology. A total of 156 ictal events were evaluated in 11 preterm (PT) and 25 fullterm (FT) infants. Most of the infants had severe abnormalities of background activity although ictal discharges occurred on both normal and abnormal backgrounds. There was a trend for a closer relationship between behavioral changes during the electroencephalographic seizure when the background activity was normal or moderately abnormal than when background activity was severely abnormal. In both PT and FT infants, the most common site of seizure origin was the temporal lobe. FT infants commonly had sharp waves, spikes, sharp and slow waves, and spike and slow waves at the onset of the ictus while rhythmic delta activity was most common in the PT infants. PT infants typically had a regional onset to the ictus whereas FT infants most frequently had a focal onset. Duration of the ictal events was similar in PT and FT infants and a change in morphology or frequency of the discharges was common during propagation of the ictal discharges in both age groups. There was not a clear relationship between onset, morphology, frequency, or propagation patterns and etiology in either the PT or FT infants. Our results demonstrate that while the type of ictal discharge is related to gestational age, there is a rich variety in the onset, morphology, and frequency of the ictal discharges in both PT and FT infants and that neonatal ictal patterns lack a close correlation with underlying pathology.

The immediate or innate immune response is the first line of defense against diverse microbial pathogens and requires the expression of recently discovered toll-like receptors (TLRs). TLR4 serves as a specific receptor for lipopolysaccharide (LPS) and is localized on the surface of a subset of mammalian cells. Although innate immunity is a necessary host defense against microbial pathogens, the consequences of its activation in the CNS can be deleterious, as we show here in a developing neural model. We examined the major non-neuronal cell types in the CNS for expression of TLR4 and found that microglia expressed high levels, whereas astrocytes and oligodendrocytes expressed none. Consistent with TLR4 expression solely in microglia, we show that microglia are the only CNS glial cells that bind fluorescently tagged lipopolysaccharide. Lipopolysaccharide led to extensive oligodendrocyte death in culture only under conditions in which microglia were present. To determine whether TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte death in mixed glial cultures, we studied cultures generated from mice bearing a loss-of-function mutation in the tlr4 gene. Lipopolysaccharide failed to induce oligodendrocyte death in such cultures, in contrast to the death induced in cultures from wild-type mice. Finally, stereotactic intracerebral injection of lipopolysaccharide into the developing pericallosal white matter of immature rodents resulted in loss of oligodendrocytes and hypomyelination and periventricular cysts. Our data provide a general mechanistic link between (1) lipopolysaccharide and similar microbial molecular motifs and (2) injury to oligodendrocytes and myelin as occurs in periventricular leukomalacia and multiple sclerosis.

The authors investigated, by means of isokinetic tests, a group of normotonic hemiparetic patients with the aim of showing the evolution, and in the short and medium term, functional markers of muscle strength and motor patterns. The results showed that the efficacy of the synchronous techniques used was good during the period of use. In the medium term, while the recovery of strength remained constant, the motor patterns deteriorated as co-contraction of antagonistic muscle groups restarted. This did not, however, lead to functional regression in comparison with the short term result (effectiveness).

In the present study the authors wanted to transfer rigorous methods of study, already in use in other sectors (sports, medicine, isokinetic work, etc.) of the validity of interventions made and their effectiveness, into an "emerging" field, that of perineal rehabilitation. 15 female patients, aged between 35 and 45, affected by stress incontinence underwent a baseline clinico-instrumental evaluation of the perineal floor including a computerized test of endurance. The patients then embarked upon a standardized rehabilitative perineal training lasting a month and at the end underwent an identical evaluation as that performed at the outset. Statistical analysis of the results obtained showed an objective improvement in the parameters considered (endovaginal pressure and its variations during a series of intermittent static contractions) quantitatively supporting clinical evidence.